Most Genetic Epidemiology Branch investigations evaluate the contributions of host susceptibility and environmental exposure in the development of cancer. In family studies, the host susceptibility measure is frequently an alteration in specific gene(s). These studies tend to be very long term with varying activity. Although two genes associated with melanoma susceptibility have been identified (CDKN2A and CDK4), alterations in these genes are found in only a small percentage of melanoma-prone families. The search for other genes continues; in collaboration with an international consortium, a search for a new melanoma susceptibility gene on 1p22 continues. We showed that the risk of pancreatic cancer within melanoma-prone families with CDKN2A mutations may be related to the site of the mutation within the ankyrin repeats and are following up the observation with more extensive analyses within the melanoma genetics consortium. We continue to accrue and evaluate new families. Genetic analyses of Italian melanoma families from the Emilio Romagna area have shown that mutations in CDKN2A are quite rare, but variants of MC1R are important risk factors in individuals without the fair hair/skin phenotype. A whole genome scan has been completed; linkage analyses are almost completed. Additional families from the Mediterranean areas may be included to refine areas of potential linkage. We have continued to evaluate families of individuals with heritable retinoblastoma and melanoma.[unreadable] [unreadable] The study of familial chordoma, a rare, low-grade, malignant bone tumor derived from remnants of the notochord, was expanded to include additional families. Additional efforts to identify more families have been initiated. Sequencing of candidate genes in the identified linkage interval continues.[unreadable] [unreadable] Studying families with lymphoproliferative cancers has been a long-standing interest. We have conducted a linkage analysis on suitable CLL kindreds which identified several areas of interest for further study. We are genotyping additional families to clarify which areas of interest to pursue. As part of the consortium to study familial CLL, we continue to develop collaborations to identify additional families. We have also developed a consensus for the nomenclature of a potential precursor condition for CLL, Monoclonal B-cell Lymphocytosis or MBL. We have conducted a whole genome linkage scan of Hodgkin lymphoma and Waldenstrom's Macroglobulinemia. The linkage analyses have identified areas of interest, with some overlap. A pilot study to identify additional Hodgkin lymphoma families is being conducted. [unreadable] [unreadable] We have continued working with the Urologic Oncology Branch in the evaluation of families with renal cancers. We have identified unique fumarate hydratase mutations in families with Hereditary Leiomyomatosis and Renal Cell Cancer in North America. We are evaluating the risk factors for uterine leiomyomas and leiomyosarcomas in these family members. Most of the data collection has been done.